ClinVar Miner

Submissions for variant NM_006306.3(SMC1A):c.3197G>A (p.Arg1066His) (rs1556886034)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623215 SCV000742807 likely pathogenic Inborn genetic diseases 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000707530 SCV000836631 pathogenic Congenital muscular hypertrophy-cerebral syndrome 2018-03-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1066 of the SMC1A protein (p.Arg1066His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been found to be de novo in an individual with clinical features consistent with SMC1A-related disorders (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg1066Cys) has been determined to be pathogenic (PMID: 25356970). This suggests that the arginine residue is critical for SMC1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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