NM_006306.4(SMC1A):c.3460G>A (p.Val1154Ile) AND Congenital muscular hypertrophy-cerebral syndrome

Clinical significance:Uncertain significance (Last evaluated: Nov 30, 2019)

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.3460G>A (p.Val1154Ile)]

NM_006306.4(SMC1A):c.3460G>A (p.Val1154Ile)

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.3460G>A (p.Val1154Ile)
  • NC_000023.11:g.53381065C>T
  • NG_006988.2:g.46606G>A
  • NM_001281463.1:c.3394G>A
  • NM_006306.4:c.3460G>AMANE SELECT
  • NP_001268392.1:p.Val1132Ile
  • NP_006297.2:p.Val1154Ile
  • LRG_773t1:c.3394G>A
  • LRG_773t2:c.3460G>A
  • LRG_773:g.46606G>A
  • LRG_773p1:p.Val1132Ile
  • NC_000023.10:g.53407986C>T
  • NM_006306.3:c.3460G>A
Protein change:
Molecular consequence:
  • NM_001281463.1:c.3394G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006306.4:c.3460G>A - 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)
SCV001224652Invitaecriteria provided, single submitter
Uncertain significance
(Nov 30, 2019)
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, SCV001224652.2

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


This sequence change replaces valine with isoleucine at codon 1154 of the SMC1A protein (p.Val1154Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SMC1A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Val1154 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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