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Repeated Sequences#

Repeated sequence: a sequence where, compared to a reference sequence, a segment of one or more nucleotides (the repeat unit) is present several times, one after the other.

Syntax#

NOTE: a Community Consultation proposal is being prepared which will suggest to allow only the format where the entire range of the repeated sequence is indicated; so g.123_191CAG[23], not g.123CAG[23].

Unique Repeat
Syntax sequence_identifier ":" coordinate_type "." position sequence "[" total_copy_number "]"
Examples
  • NC_000014.8:g.123CAG[23]
Mixed Repeat
Syntax sequence_identifier ":" coordinate_type "." position sequence "[" total_copy_number "]" sequence "[" total_copy_number "]" … sequence "[" total_copy_number "]"
Examples
  • NC_000014.8:g.123_191CAG[19]CAA[4]
Explanation of Symbols
  • coordinate_type: The type of molecule and coordinate system; see the general recommendations.
  • position: a position specified as a simple ordinal sequence position
  • sequence: DNA, RNA, or AA sequence
  • sequence_identifier: an identifier for a sequence from a recognized database
  • total_copy_number: The total number of sequence copies in a repeat
See also explanation of grammar used in HGVS Nomenclature.

Notes#

  • repeated sequences include both small (mono-, di-, tri-, etc., nucleotide) and larger (kilobase-sized) repeats.
  • for mixed repeats, the range of the repeat sequence is given followed by a listing of each repeat unit and the number of repeats in each unit; NC_000012.11:g.112036755_112036823CTG[9]TTG[1]CTG[13].
  • NM_000044.3:c.171_239GCA[34] describes a repeated sequence containing 34 GCA units (sequenced, the reference sequence contains 23 GCA units). NM_000044.3:c.(92_331)insN[33] describes an insertion of 33 nucleotides in the amplified region from position c.92 to c.331 (not sequenced), containing a repeated sequence of 24 GCA units in the reference sequence.
  • exception: using a coding DNA reference sequence ("c." description), a repeated sequence variant description can be used only for repeat units with a length which is a multiple of 3, i.e. which can not affect the reading frame. Consequently, use NM_024312.4:c.2692_2693dup and not NM_024312.4:c.2686A[10]; use NM_024312.4:c.1741_1742insTATATATA and not NM_024312.4:c.1738TA[6]. This restriction only applies to the coding sequence, which does not include the introns or the UTR sequence. As such, NM_024312.4:c.-6_-3G[6] is valid as the reading frame is not affected.

Examples#

  • unique repeat

    • sequenced

      • NC_000014.8:g.101179660_101179695TG[14]
        a repeated TG di-nucleotide sequence, starting at position g.101179660 on human chromosome 14, with 14 TG copies.

      • NC_000014.8:g.[101179660_101179695TG[14]];[101179660_101179695TG[18]]
        a repeated TG di-nucleotide sequence, starting at position g.101179660 on human chromosome 14, is present with 14 TG copies on one allele and 18 TG copies on the other allele.

    • repeat expansion disorders

      • sequenced

        • NM_023035.2:c.6955_6993CAG[26] (or c.6955_6993dup)
          a repeated CAG tri-nucleotide sequence, starting at position c.6955 in the CACNA1A gene with 26 CAG copies (p.(Gln2319[26]) or p.(Gln2319_Gln2331dup)).

        • NC_000003.12:g.63912687_63912716AGC[13] / c.89_118AGC[13]
          a repeated AGC tri-nucleotide sequence in the ATXN7 gene on chromosome 3, starting at position g.63912687 / c.89, with 13 AGC copies (the reference sequence has 10 copies).
          NOTE: in literature, the tri-nucleotide repeat, encoding a poly-Gln repeat on protein level, is known as the CAG repeat. However, based on the ATXN7 coding DNA reference sequence (GenBank LRG_866t1 or NM_000333.3) and applying the 3'rule, the repeat has to be described as an AGC repeat.

      • not sequenced

        • NC_000003.12:g.(63912602_63912844)insN[9] / NM_000333.3:c.(4_246)insN[9]
          a fragment containing the AGC repeat in the ATXN7 gene was amplified (from nucleotide g.63912602 / c.4 to g.63912844 / c.246) and its size determined to be 9 nucleotides larger (insN[9]) compared to that of the reference sequence.
          NOTE: since the fragment was not sequenced, the variant can not be described as g.63912687_63912716AGC[13] / c.89_118AGC[13].

        • NC_000003.12:g.(63912602_63912844)delN[15] / NM_000333.3:c.(4_246)delN[15]
          a fragment containing the AGC repeat in the ATXN7 gene was amplified (from nucleotide g.63912602 / c.4 to g.63912844 / c.246) and its size determined to be 15 nucleotides smaller (delN[15]) than that of the reference sequence.

  • mixed repeat reference sequence

    • repeat expansion disorders

      • FMR1 repeat (reference sequence GGC[9]GGA[1]GGC[10])
        in literature, the Fragile-X tri-nucleotide repeat is described as a CGG-repeat. However, based on a coding DNA reference sequence (GenBank NM_002024.5) and applying the 3'rule, the repeat has to be described as a mixed GGC-GGA-GGC repeat.

        • NM_002024.5:c.-128_-69GGC[10]GGA[1]GGC[9]GGA[1]GGC[10]
          a sequenced GGC tri-nucleotide repeat from position c.-128 to c.-69 contains 10 GGC, 1 GGA, 9 GGC, 1 GGA, and 10 GGC units (31 repeat units).

        • NM_002024.5:c.-128_-69GGC[68]GGA[1]GGC[10]
          a repeated CGG tri-nucleotide sequence, starting at position c.-129 with 79 repeat units.
          NOTE: since the reference sequence contains a mixed repeat (CGG and AGG units), the variant can not be described as NM_002024.5:c.-129CGG[79]. NM_002024.5:c.-129CGG[79] would cover only the sequence up to the first AGG interruption (position c.-99).

        • NM_002024.5:c.-128_-69GGM[108]
          a repeated mixed tri-nucleotide sequence, starting at position c.-129 with 108 GGC / GGA copies.

        • NM_002024.5:c.(-144_-16)insN[(1800_2400)]
          the amplified region containing the FMR1 repeat region (between nucleotides c.-144 and c.-16) contains an insertion of 1800 to 2400 nucleotides (600 to 800 GGC / GGA units).

      • HTT repeat (reference sequence LRG_763t1:c.52_153CAG[21]CAA[1]CAG[1]CCG[1]CCA[1]CCG[7]CCT[2])
        in literature, the Huntington's Disease tri-nucleotide repeat, encoding a variable poly-Gln followed by a variable poly-Pro repeat on protein level, is known as the CAG repeat. Based on the HTT (huntingtin) coding DNA reference sequence (GenBank LRG_763t1 or NM_002111.8) and applying the 3'rule, the Poly-Gln encoding repeat has to be described as an AGC-AAC-AGC repeat.

        • LRG_763t1:c.54_110GCA[23]
          a sequenced GCA tri-nucleotide repeat starting at position c.54 contains 23 units, on protein level described as NP_002102.4:p.(Gln18)[25].
          NOTE: the GCA repeat is followed by ACAGCA, extending the encoded Gln-repeat by 2.

      • CFTR intron 9
        NM_000492.3:c.1210-33_1210-6GT[11]T[6]
        the mixed repeat sequence form position c.1210-33 to c.1210-6 contains 11 GT and 6 T copies.
        NOTE: when only the variable T-stretch is described, the format is NM_000492.3:c.1210-12_1210-6T[7] (see Q&A below).

    • NC_000012.11:g.112036755_112036823CTG[9]TTG[1]CTG[13]
      a complex repeated sequence from position g.112036755 to g.112036823 on chromosome 12 with first a CTG unit present in 9 copies, then a TTG unit present in 1 copy and then a CTG unit present in 13 copies.

  • differing genomic (g.) and coding DNA (c.) descriptions
    NC_000001.11:g.57367047_57367121ATAAA[15] and NM_021080.3:c.-136-75952_-136-75878ATTTT[15] describe the same repeat allele in intron 3 of the DAB1 gene.
    NOTE: based on the 3' rule and the transcriptional orientation of the gene (minus strand), the description of the repeat units differs.

Discussion#

Intron 9 of the CFTR gene ends with the sequence ...tgtgtgtgtgtttttttaacag. Both the TG and T stretches are variable in length (from 9 to 13 and 5 to 9, respectively). The reference sequence has 11 TG copies and 7 Ts. Is it correct to describe an allele as c.1210-14TG[13]T[5] or for the T stretch as c.1210-6T[5]?

A complex case. First, note that by applying the 3'rule it is a variable GT and not a TG stretch. When the coding DNA reference sequence has 11 TG copies followed by 7 T copies, the reference allele is described as c.1210-33_1210-6GT[11]T[6]. When only variability of the T-stretch is reported, the reference allele is described as c.1210-12_1210-6T[7].

To indicate the overall variability found in the population, the description is c.1210-33_1210-6GT[(9_13)]T[(4_8)] for the combined repeat and c.1210-12_1210-6T[(5_9)] for the T-stretch.