Submissions for variant NM_198525.3(KIF7):c.1220C>A (p.Ala407Asp)

gnomAD frequency: 0.00286  dbSNP: rs587780375

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117411	SCV000151609	uncertain significance	not provided	2013-09-16	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000117411	SCV000331870	uncertain significance	not provided	2017-03-09	criteria provided, single submitter	clinical testing
Invitae	RCV001083297	SCV000636817	likely benign	Acrocallosal syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199843	SCV001370567	likely benign	not specified	2020-05-08	criteria provided, single submitter	clinical testing	Variant summary: KIF7 c.1220C>A (p.Ala407Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 137568 control chromosomes, predominantly at a frequency of 0.0084 within the African or African-American subpopulation in the gnomAD database (v3 genomes dataset), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in KIF7 causing Acrocallosal Syndrome/Joubert Syndrome 12 phenotype (0.0004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1220C>A has been reported in the literature in one individual affected with cerebellar ataxia (Sun_2019). This report did not provide unequivocal conclusions about association of the variant with Acrocallosal Syndrome/Joubert Syndrome 12. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000117411	SCV001754078	likely benign	not provided	2021-06-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29915382)
Ambry Genetics	RCV002528215	SCV003682232	likely benign	Inborn genetic diseases	2021-07-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.