Submissions for variant NM_001378454.1(ALMS1):c.9886A>G (p.Thr3296Ala)

gnomAD frequency: 0.00296  dbSNP: rs58806616

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461539	SCV000554297	benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000413135	SCV000708536	benign	not specified	2017-05-15	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172529	SCV001335582	benign	Monogenic diabetes	2018-03-16	criteria provided, single submitter	research	ACMG criteria: PP3 (6 predictors), BP4 (3 predictors), BS1 (1.13% in 1000G African population and disease frequency is 1 in 10,000), BS2 (4 homozygotes in gnomAD)=benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000413135	SCV001363237	benign	not specified	2019-07-15	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.9883A>G (p.Thr3295Ala, also known as c.9889A>G) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 249334 control chromosomes, predominantly at a frequency of 0.0098 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.9883A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classified it as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000413135	SCV001365658	likely benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Thr3295Ala in exon 12 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.93% (91/9788) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs58806616).
GeneDx	RCV001692093	SCV001912356	benign	not provided	2019-05-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379270	SCV002693243	likely benign	Cardiovascular phenotype	2019-06-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000461539	SCV003928175	uncertain risk allele	Alstrom syndrome		criteria provided, single submitter	research	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs58806616 in Alstrom syndrome yet.
GeneDx	RCV000413135	SCV000491838	uncertain significance	not specified	2016-11-21	flagged submission	clinical testing	A variant of uncertain significance has been identified in the ALMS1 gene. The T3297A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T3297A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, the Exome Aggregation Consortium (ExAC) reports T3297A was observed in 91/9,788 (0.9%) alleles from individuals of African background, including one homozygous individual, indicating it may be a rare benign variant in this population. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Natera, Inc.	RCV000461539	SCV001459595	benign	Alstrom syndrome	2020-01-01	no assertion criteria provided	clinical testing