NM_006306.4(SMC1A):c.3344G>T (p.Cys1115Phe) AND Congenital muscular hypertrophy-cerebral syndrome

Clinical significance:Likely pathogenic (Last evaluated: Oct 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_006306.4(SMC1A):c.3344G>T (p.Cys1115Phe)]

NM_006306.4(SMC1A):c.3344G>T (p.Cys1115Phe)

SMC1A:structural maintenance of chromosomes 1A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_006306.4(SMC1A):c.3344G>T (p.Cys1115Phe)
  • NC_000023.11:g.53382325C>A
  • NG_006988.2:g.45346G>T
  • NM_001281463.1:c.3278G>T
  • NM_006306.4:c.3344G>TMANE SELECT
  • NP_001268392.1:p.Cys1093Phe
  • NP_006297.2:p.Cys1115Phe
  • LRG_773t1:c.3278G>T
  • LRG_773:g.45346G>T
  • LRG_773p1:p.Cys1093Phe
  • NC_000023.10:g.53409246C>A
Protein change:
Molecular consequence:
  • NM_001281463.1:c.3278G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006306.4:c.3344G>T - missense variant - [Sequence Ontology: SO:0001583]


Congenital muscular hypertrophy-cerebral syndrome (CDLS2)
Cornelia de Lange syndrome 2
MONDO: MONDO:0010370; MedGen: C1802395; Orphanet: 199; OMIM: 300590

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001577400Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 9, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV001577400.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)


This sequence change replaces cysteine with phenylalanine at codon 1115 of the SMC1A protein (p.Cys1115Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMC1A-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMC1A protein function. This variant disrupts the p.Cys1115 amino acid residue in SMC1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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