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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.
Description
NOTE: a Community Consultation is prepared which will suggest to allow only one format where the entire range of the repeated sequence must be indicated, e.g. g.123_191CAG[23] not g.123CAG[23]
Format (unique repeat): “prefix”“position_first_nucleotide_first_repeat_unit”“repeat_sequence”[“copy_number”], e.g. g.123CAG[23]
“prefix” = reference sequence used = g.
“position_first_nucleotide_first_repeat_unit” = first nucleotide of first repeat unit = 123
“repeat_sequence” = sequence repeat unit = CAG
[ = opening symbol for copy number allele = [
“copy_number” = number of repeat units = 23
] = closing symbol for copy number allele = ]
Format (mixed repeat): “prefix”“range_repeated_sequence”“repeat_sequence_unit1”[“copy_number”]”repeat_sequence_unit2”[“copy_number”]”…“, e.g. g.123_191CAG[19]CAA[4]
“prefix” = reference sequence used = g.
“range_repeated_sequence” = position first to last nucleotide repeated sequence (range) = 123_191
“repeat_sequence_unit1” = sequence first repeat unit = CAG
[ = opening symbol for allele = [
“copy_number” = number of repeat units = 19
] = closing symbol for allele = ]
“repeat_sequence_unit2” = sequence first repeat unit = CAA
[ = opening symbol for allele = [
“copy_number” = number of repeat units = 4
] = closing symbol for allele = ]
… = and so on for repeat_sequence_unit3, repeat_sequence_unit4, etc.
Note
reference sequences accepted are g., o. m., c. and n. (genomic, mitochondrial, coding DNA and non-coding DNA)
for mixed repeats the range of the reapeat 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.171GCA[23] describes a repeated sequence containing 23 GCA units (sequenced). NM_000044.3:c.(92_331)insN[33] describes an insertion of 3 nucleotides, in the amplified region from position c.92 to c.331 (not sequenced), of a repeated sequence containing 24 GCA units.
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.101179660TG[14]
a repeated TG di-nucleotide sequence starting at position g.101179660 on human chromosome 14, with 14 TG copies
NC_000014.8:g.[101179660TG[14]];[101179660TG[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
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.63912687AGC[13] | c.89AGC[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
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]” ) then that of the reference sequence.
NOTE: since the fragment was not sequenced the variant can not be described as g.63912687AGC[13] / c.89AGC[13].
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]” ) then that of the reference sequence.
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
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.-129CGG[79]
a repeated CGG tri-nucleotide sequence starting at position c.-129 with 79 CGG copies
NOTE: by definition, since the reference sequence contains a mixed repeat (CGG and AGG units), the variant description only covers the sequence up to the first AGG interruption (position c.-99). A better description, giving less confusion, is NM_002024.5:c.-128_-69GGC[78]GGA[1]GGC[10] (i.e. assuming only the length of the first CGG segment was meant and not the total length of the GGC-GGA-GGC repeat).
NM_002024.5:c.-128GGM[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)
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.53AGC[23]
a sequenced AGC tri-nucleotide repeat starting at position c.53 contains 23 units, on protein level described as NP_002102.4:p.(Gln18)[25]
NOTE: the AGC repeat is followed by AACAGC 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.1210-12T[7] (see Q&A below)
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_000001.10:g.57832719ATAAA[15] and NM_021080.3:c.-136-75952ATTTT[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
Q&A
Intron 9 of the CFTR gene ends with the sequence ...tgtgtgtgtgtttttttaacag[exon_10]. Both the TG and T stretches are variable in length (from 9 to 13 and 5 to 9 resp.). The reference sequence has 11 TG copies and 7 T's. 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 TG stretch. When the coding DNA reference sequence has TG11 followed by T7, 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.1210-12T[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.1210-12T[5_9] for the T-stretch.