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].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.
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.
